Cyclopentane heptan (ENE)OIC acid, 2-heteroarylalkenyl derivatives as therapeutic agents

ABSTRACT

The present invention provides cyclopentane heptanoic acid, 2 heteroaryl alkyl or alkenyl derivatives which may be substituted in the 1-position with hydroxyl, alkyloxy, amino and amido groups, e.g. 1-OH cyclopentane heptanoic acid, 2 heteroarylalkenyl derivatives. In particular, these derivatives are 7-[5-hydroxy-2-(heteroatom-substituted hydroxyhydrocarbyl)-3-hydroxycyclopentyl] heptanoic or heptenoic acids and amine, amide, ether, ester and alchohol derivatives of said acids wherein one or more of said hydroxy groups are replaced with an ether group. These compounds are potent ocular hypotensive and are particularly suited for the management of glaucoma. Moreover, the compounds of this invention are smooth muscle relaxants with broad application in systemic hypertensive and pulmonary diseases; with additional application in gastrointestinal disease, reproduction, fertility, incontinence, shock, inflammation, immune regulation, disorder of bone metabolism, renal dysfunction, cancer and other hypoproliferative diseases.

CROSS REFERENCE TO RELATED PATENT APPLICATIONS

[0001] This patent application is a continuation of U.S. patentapplication Ser. No. 08/608,794 which was filed on Feb. 29, 1996 in thename of Burk.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention provides cyclopentane heptanoic add, 2heteroaryl alkyl or alkenyl derivatives which may be substituted in the1-position with hydroxyl, alkyloxy, amino and amido groups, e.g. 1-OHcyclopentane heptanoic acid, 2 heteroarylalkenyl derivatives. Inparticular, these derivatives are 7-[5-hydroxy-2-(heteroatom-substitutedhydroxyhydrocarbyl)-3-hydroxycyclopentyl] heptanoic or heptenoic acidsand amine, amide, ether, ester and alcohol derivatives of said acidswherein one or more of said hydroxy groups are replaced with an ethergroup. These compounds are potent ocular hypotensives and areparticularly suited for the management of glaucoma. Moreover, thecompounds of this invention are smooth muscle relaxants with broadapplication in systemic hypertensive and pulmonary diseases; withadditional application in gastrointestinal disease, reproduction,fertility, incontinence, shock, inflammation, immune regulation,disorder of bone metabolism, renal dysfunction, cancer and otherhyperproliferative diseases.

[0004] 2. Description of Related Art

[0005] Ocular hypotensive agents are useful in the treatment of a numberof various ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

[0006] Glaucoma is a disease of the eye characterized by increasedintraocular pressure. On the basis of its etiology, glaucoma has beenclassified as primary or secondary. For example, primary glaucoma inadults (congenital glaucoma) may be either open-angle or acute orchronic angle-closure. Secondary glaucoma results from pre-existingocular diseases such as uveitis, intraocular tumor or an enlargedcataract.

[0007] The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure angle-closure glaucoma, theanterior chamber is shallow, the filtration angle is narrowed, and theiris may obstruct the trabecular meshwork at the entrance of the canalof Schlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

[0008] Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

[0009] Considering all types together, glaucoma occurs in about 2% ofall persons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical b-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

[0010] Certain eicosanoids and their derivatives have been reported topossess ocular hypotensive activity, and have been recommended for usein glaucoma management. Eicosanoids and derivatives include numerousbiologically important compounds such as prostaglandins and theirderivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

[0011] Various types of prostaglandins are known, depending on thestructure and substituents carried on the alicyclic ring of theprostanoic acid skeleton. Further classification is based on the numberof unsaturated bonds in the side chain indicated by numerical subscriptsafter the generic type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [[e.g. prostaglandinF_(2α)(PGF_(2α))].

[0012] Prostaglandins were earlier regarded as potent ocularhypertensives, however, evidence accumulated in the last decade showsthat some prostaglandins are highly effective ocular hypotensive agents,and are ideally suited for the long-term medical management of glaucoma(see, for example, Bito, L. Z. Biological Protection withProstaglandins, Cohen, M. M., ed., Boca Raton, Fla., CRC Press Inc.,1985, pp. 231-252; and Bito, L. Z., Applied Pharmacology in the MedicalTreatment of Glaucomas Drance, S. M. and Neufeld, A. H. eds., New York,Grune & Stratton, 1984, pp. 477-505. Such prostaglandins includePGF_(2α), PGF_(1α), PGE_(2,) and certain lipid-soluble esters, such asC₁ to C₂ alkyl esters, e.g. 1-isopropyl ester, of such compounds.

[0013] Although the precise mechanism is not yet known experimentalresults indicate that the prostaglandin-induced reduction in intraocularpressure results from increased uveoscleral outflow [Nilsson et.al.,Invest. Ophthalmol. Vis. Sci. (suppl), 284 (1987)].

[0014] The isopropyl ester of PGF_(2α)has been shown to havesignificantly greater hypotensive potency than the parent compound,presumably as a result of its more effective penetration through thecornea. In 1987, this compound was described as “the most potent ocularhypotensive agent ever reported” [see, for example, Bito, L. Z., Arch.Ophthalmol. 105. 1036 (1987), and Siebold et.al., Prodrug 5 3 (1989)].

[0015] Whereas prostaglandins appear to be devoid of significantintraocular side effects, ocular surface (conjunctival) hyperemia andforeign-body sensation have been consistently associated with thetopical ocular use of such compounds, in particular PGF_(2α)and itsprodrugs, e.g., its 1-isopropyl ester, in humans. The clinicalpotentials of prostaglandins in the management of conditions associatedwith increased ocular pressure, e.g. glaucoma are greatly limited bythese side effects.

[0016] In a series of co-pending United States patent applicationsassigned to Allergan, Inc. prostaglandin esters with increased ocularhypotensive activity accompanied with no or substantially reducedside-effects are disclosed. The co-pending U.S. Ser. No. 596,430 (filedOct. 10, 1990), relates to certain 11l-acyl-prostaglandins, such as11-pivaloyl, 11-acetyl, 1111-isobutyryl, 11-valeryl, and 11-isovalerylPGF_(2α). Intraocular pressure reducing 15-acyl prostaglandins aredisclosed in the co-pending application U.S. Ser. No. 175,476 (filedDec. 29, 1993). Similarly, 11,15-9,15 and 9,11-diesters ofprostaglandins, for example 11,15-dipivaloyl PGF_(2α)are known to haveocular hypotensive activity. See the co-pending patent applications U.S.Ser Nos. 385,645 (filed Jul. 07, 1989, now U.S. Pat. No. 4,994,274),584,370 (filed Sep. 18, 1990, now U.S. Pat. No. 5,028,624) and 585,284(filed Sep. 18 1990, now U.S. Pat. No. 5,034,413).

[0017] Other patents and patent applications assigned to Allergan, Inc.disclose and claim other compounds which are useful in treatingincreased intraocular pressure and thus are useful in the treatment ofglaucoma. Said patents and patent applications include U.S. patentapplication Ser. No. 08/174,535, which is entitled Cyclopentane (ene)Heptenoic or Heptanoic Acids and Derivatives Thereof Useful asTherapeutic Agents and was filed on Dec. 28, 1993 and U.S. patentapplication Ser. No. 08/443,992, which is entitled CyclopentaneHeptan(ene) oic Acid, 2-Heteroarylalkenyl Derivatives as TherapeuticAgents and was filed on May 18, 1995.

[0018] The disclosures of all of these patent applications are herebyexpressly incorporated by reference.

SUMMARY OF THE INVENTION

[0019] The present invention concerns a method of treating ocularhypertension which comprises administering to a mammal having ocularhypertension a therapeutically effective amount of a compound of formulaI

[0020] wherein the wavy segments represent an α or β bond, dashed linesrepresent a double bond or a single bond, R is a heteroaryl radical or asubstituted heteroaryl radical, R¹ is hydroxyl or a hydrocarbyloxy orheteroatom sustituted hydrocarbyloxy comprising up to 20, e.g. up to 10carbon atoms, and preferably a lower alkyloxy radical having up to sixcarbon atoms, X is selected from the group consisting of −OR⁶ and−N(R⁶)2, wherein R⁶ is hydrogen or a lower alkyl radical having from 1to 6 carbon atoms and Y is ═O or represents 2 hydrogen radicals andfurther provided that at least one of R¹ is a hydrocarbyloxy orheteroatom substituted hydrocarbyloxy.

[0021] In particular, the substituents on the heteroaryl radical may beselected from the group consisting of lower alkyl, e.g. C₁ to C₆ alkyl;halogen, e.g. fluoro, chloro, iodo and bromo; trifluoromethyl (CF₃);COR⁷ ₁ e.g. COCH_(3;) COCF_(3;) SO₂NR⁷ ₁ SO2NH2; NO_(2;) CN; etc.,wherein R⁷ is a lower alkyl radical having from 1 to 6 carbon atoms.

[0022] In a further aspect, the present invention relates to anophthalmic solution comprising a therapeutically effective amount of acompound of formula (I), wherein the symbols have the above meanings, ora pharmaceutically acceptable salt thereof, in admixture with anon-toxic, ophthalmically acceptable liquid vehicle, packaged in acontainer suitable for metered application.

[0023] In a still further aspect, the present invention relates to apharmaceutical product, comprising

[0024] a container adapted to dispense its contents in a metered form;and

[0025] an ophthalmic solution therein, as hereinabove defined.

[0026] A further aspect of the present invention provides methods oftreating cardiovascular, pulmonary-respiratory, gastrointestinal,productive, allergic disease, shock and ocular hypertension whichcomprises administering an effective amount of a compound represented bythe formula I.

[0027] Finally, certain of the compounds represented by the aboveformula, disclosed below and utilized in the methods of the presentinvention are novel and unobvious.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0028]FIG. 1 is a schematic of the chemical synthesis of certain1-carboxylic acid compounds and ester derivatives thereof specificallydisclosed as Example 4(a)-(e) and 5(a)-(e) below.

[0029]FIG. 2 is a schematic of the chemical synthesis of certain 1-amidocompounds specifically disclosed as Examples 6(b)-(g) below.

[0030]FIG. 3 is a schematic of the chemical synthesis of certain1-isopropyl ester compounds specifically disclosed as Examples 7(f)-(i),below.

[0031]FIG. 4 is a schematic of the chemical synthesis of certain15-methoxy-substituted carboxylic acid compounds and isopropylderivatives thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention relates to the use of cyclopentaneheptan(ene)oic acid, 2-heteroaryl alkyl or alkenyl derivatives astherapeutic agents, e.g. as ocular hypotensives. The compounds used inaccordance with the present invention are encompassed by the followingstructural formula I:

[0033] wherein the substituents and symbols are as hereinabove defined.

[0034] Preferably, the compounds used in accordance with the presentinvention have the following structural formula II:

[0035] wherein the hatched segments represent α bonds, the solidtriangle represents a β bond and the substituents and symbols are ashereinabove defined. The dotted lines on bonds between carbons 5 and 6(C-5) and carbons 13 and 14 (C-13) indicate a single or double bond. Iftwo solid lines are used at C-5, or C-13, it indicates a specificconfiguration for that double bond. Hatched lines used at position C-8,C-9 and C-11 indicate the α configuration. A triangle at position C-12represents β orientation. A more preferred group of the compounds of thepresent invention includes compounds that have the following structuralformula III:

[0036] wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen, and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6

[0037] carbon atoms, or, together with

[0038] , R³ and R⁴ forms a condensed aryl ring and R⁵ is a lower alkylhaving from 1 to 6 carbon atoms. Preferably, when X is —N(R⁶)2, Y is ═O.

[0039] More preferably, R⁵ is methyl and at least one of R², R³ or R⁴are independently selected from the group consisting of chloro, bromoand lower alkyl. In one aspect of the invention, at least one of R², R³or R⁴ is chloro or bromo, and more preferably at least one of R², R³ orR⁴ is bromo or at least two of R² ₁ R³ or R⁴ are chloro or bromo. Inanother aspect of this invention, at least one of R², R³ or R⁴ is ethyl,propyl, or butyl.

[0040] Another preferred group includes compounds having the formula IV:

[0041] The above compounds of the present invention may be prepared bymethods that are known in the art or according to the working examplesbelow. The compounds, below, are especially preferred representative ofthe compounds of the present invention.

[0042]7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-(2-methyl)-thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0043]7-[3α,50α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0044] Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate.

[0045] A pharmaceutically acceptable salt is any salt which retains theactivity of the parent compound and does not impart any deleterious orundesirable effect on the subject to whom it is administered and in thecontext in which it is administered. Of particular interest are saltsformed with inorganic ions, such as sodium, potassium, calcium,magnesium and zinc.

[0046] Pharmaceutical compositions may be prepared by combining atherapeutically effective amount of at least one compound according tothe present invention, or a pharmaceutically acceptable acid additionsalt thereof, as an active ingredient, with conventional ophthalmicallyacceptable pharmaceutical excipients, and by preparation of unit dosageforms suitable for topical ocular use. The therapeutically efficientamount typically is between about 0.0001 and about 5% (w/v), preferablyabout 0.001 to about 1.0% (w/v) in liquid formulations.

[0047] For ophthalmic application, preferably solutions are preparedusing a physiological saline solution as a major vehicle. The pH of suchophthalmic solutions should preferably be maintained between 6.5 and 7.2with an appropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

[0048] Preferred preservatives that may be used in the pharmaceuticalcompositions of the present invention include, but are not limited to,benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetateand phenylmercuric nitrate. A preferred surfactant is, for example,Tween 80. Likewise, various preferred vehicles may be used in theophthalmic preparations of the present invention. These vehiclesinclude, but are not limited to, polyvinyl alcohol, povidone,hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose,hydroxyethyl cellulose and purified water.

[0049] Tonicity adjustors may be added as needed or convenient. Theyinclude, but are not limited to, salts, particularly sodium chloride,potassium chloride, mannitol and glycerin, or any other suitableophthalmically acceptable tonicity adjustor.

[0050] Various buffers and means for adjusting pH may be used so long asthe resulting preparation is ophthalmically acceptable. Accordingly,buffers include acetate buffers, citrate buffers, phosphate buffers andborate buffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

[0051] In a similar vein, an ophthalmically acceptable antioxidant foruse in the present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

[0052] Other excipient components which may be included in theophthalmic preparations are chelating agents. The preferred chelatingagent is edentate disodium, although other chelating agents may also beused in place or in conjunction with it.

[0053] The ingredients are usually used in the following amounts:Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative   0-0.10 vehicle    0-40 tonicity adjustor    1-10 buffer  0.01-10 pHadjustor q.s. pH  4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%

[0054] The actual dose of the active compounds of the present inventiondepends on the specific compound, and on the condition to be treated;the selection of the appropriate dose is well within the knowledge ofthe skilled artisan.

[0055] The ophthalmic formulations of the present invention areconveniently packaged in forms suitable for metered application, such asin containers equipped with a dropper, to facilitate the application tothe eye. Containers suitable for dropwise application are usually madeof suitable inert, non-toxic plastic material, and generally containbetween about 0.5 and about 15 ml solution.

[0056] The invention is further illustrated by the followingnon-limiting Examples, which are summarized in the reaction schemes ofFIGS. 1 through 4, wherein the compounds are identified by the samedesignator in both the Examples and the Figures.

[0057] Compound 5a

[0058]7-[3α,5α,-Dihydroxy-2-(3α-hydroxy-5-(2-(3-chloro)benzothienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid

[0059] Step 1: Preparation of Enone 2a

[0060] To a suspension of sodium hydride (27 mg, 1.15 mmol) intetrahydrofuran (THF) (2.0 mL) cooled to 0° C. was added dimethyl4-(2-(3-chloro) benzothienyl)-2-oxo-butylphosphonate(363 mg, 1.15 mmol)in THF (2.2 mL). (In this Example, benzothienyl is an example of thehetero aryl radicals represented by R in the disclosure and claims andAr in the Figures.) After 0.25 h a solution of the aldehyde 1 (507 mg,1.04 mmol) in THF (2.0 mL) was added and the reaction was allowed toslowly warm to 23° C. over a period of 8 h. (In FIG. 1 THP representstetrahydropyranyl.) The reaction solution was quenched with saturatedaqueous NH4Cl and extracted with ethyl acetate (EtOAc.) The aqueousphase was made slightly acidic and extracted again with EtOAc. Thecombined organics were washed with brine, dried over MgSO4, filtered andconcentrated in vacuo. Flash column chromatography (silica gel, 2:1hexane/EtOAc) gave 729 mg of enone 2a.

[0061] Step 2: Preparation of alcohol 3a

[0062] Sodium tetrahydridoborate (40 mg, 1.05 mmol) was added to asolution of the enone (729 mg, 1.05 mmol) in methanol (MeOH)(2.1 mL) at0° C. After 2 h the solvent was removed in vacuo and the residue wasstirred with 1N NaOH and EtOAc for 0.5 h. The organic portion wasseparated, dried over MgSO4, filtered and concentrated in vacuo. Theα-alcohol 3a was separated by flash column chromatography or HPLC(silica gel, 3:1 hexane/EtOAc).

[0063] Step 3: Preparation of Triol 4a

[0064] A solution of the alcohol 3a and pyridinium p-toluene sulfonate(PPTs) (53 mg, 0.212 mmol) in MeOH(0.4 mL) was heated at 40° C. for 4 h.The solvent was removed in vacuo and the residue was diluted with EtOAcand then washed with 1N HCl, saturated aqueous NaHCO₃ and brine. Theorganic portion was dried over MgSO4, filtered and concentrated in vacuothe triol 4a.

[0065] Step 4: Preparation of Carboxlic Acid 5a

[0066] The triol 4a was diluted with THF (0.8 mL) and lithium hydroxide(0.4 mL of a 0.5 N solution in H₂O, 0.186 mmol) was added. After 16 hthe reaction was acidified with 1N HCl and extracted with EtOAc. Theorganic portion was washed with brine, dried over MgSO4, andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica gel, 9:1 EtOAc/MeOH) to give 14.0 mg of free acid5a.

[0067] By methods described for compound 5a, steps 1 through 4, thefollowing compounds were prepared as illustrated in Scheme 1:

[0068] Compound 5b

[0069]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0070] Prepared according to the procedures described above for 5aexcept the use of dimethyl4-(5-(2,3-dibromo)thienyl)-2-oxo-butylphosphonate afforded 45 mg of freeacid 5b.

[0071] Compound 5c

[0072]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-methyl)furanyl-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0073] Prepared according to the procedures described above for 5aexcept the use of dimethyl4-(5-(2-methyl)furanyl)-2-oxo-butylphosphonate afforded 63.6 mg of freeacid 5c.

[0074] Compound 5d

[0075]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0076] Prepared according to the procedures described above for 5aexcept the use of dimethyl4-(3-(2,5-dibromo)thienyl)-2-oxo-butylphosphonate afforded 74 mg of freeacid 5d.

[0077] Compound 5e

[0078]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-bromo-3-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.

[0079] Prepared according to the procedures described above for 5aexcept the use of dimethyl4-(5-(2-bromo-3-methyl)thienyl)-2-oxobutylphos-phonate afforded 40.6 mgof free acid 5e

[0080] Synthesis of Amides 6b-g (Scheme 2)

[0081] Compound 6b

[0082]7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2,3-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0083] The 3a-triol 4b (27mg, 0.048 mmol) isolated from step 3 duringsynthesis of 5b, was placed in a tube with ammonium chloride (76 mg,1.42 mmol). Ammonia gas -4.5 mL was condensed into the tube at −70° C.The tube was sealed and heated to 65° C. for 16 h. The tube was cooledto -70° C., vented and the ammonia allowed to evaporate on its ownaccord. The residue was dissolved in 1:1 EtOAc/H₂O. The organic portionwas separated, dried over MgSO4, filtered and concentrated in vacuo.Flash column chromatography (silica gel, 9:1 CH₂Cl₂/MeOH) gave 16.8 mgof the title compound 6b.

[0084] Compound 6c

[0085] 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-methyl)furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0086] According to the procedures described above for preparation of 6bthe 3α-triol 4c (51 mg, 0.126 mmol) was converted to 25.1 mg of thetitle compound 6c.

[0087] Compound 6d

[0088] 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2,5-dibromo)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0089] According to the procedures described above for the preparationof 6b the 3α-triol 4d (24 mg, 0.42 mmol) was coverted to 12 mg of thetitle compound 6d.

[0090] Compound 6e

[0091] 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-bromo-3-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0092] According to the procedures described above for the preparationof 6b the 3α-triol 4e (63 mg, 0.126 mmol) was converted to 33 mg of thetitle compound 6e.

[0093] Compound 6f

[0094] 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0095] According to the procedures described above for the preparationof 6b Methyl ⁷-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(2-furanyl)-1E-pentenyl) cyclopentyl]-5Z-heptenoate 4f (50 mg, 0.127 mmol) was coverted to 12 mg of the titlecompound 6f.

[0096] Compound 6g

[0097] 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenamide.

[0098] According to the procedures described above for preparation of 6bMethyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate4 g (65 mg, 0.154 mmol) was converted to 35.8 mg of the tilte compound6g.

[0099] The isopropyl esters 7f-i were prepared as illustrated in Scheme3 from the corresponding carboxylic acids 5f-i, which were prepared inan analogous manner to carboxylic acids 5a-e:

[0100] Compound 7f

[0101] Isopropyl 7-[3α,5α-Dihydroxy-2-(3a-hydroxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate.

[0102] A solution of the previously prepared carboxylic acid 5f (11.0mg, 0.029 -mmol) and O-isopropyl-N, N′-diisopropylisourea (270 mg. 1.45mmol) in benzene (1.5 mL) was heated to 75° C. for 4 h. The reactionmixture was concentrated in vacuo and the residue was purified by flashcolumn chromatography (silica gel, 100% EtOAc) to afford 3.7 mg of thetitle compound 7f.

[0103] Compound 7g

[0104] Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(4-(2-methyl)thienyl-1E-pentenyl)cyclopentyl]-5Z-heptenoate.

[0105] According to the procedures described above for the preparationof 7f the previously prepared carboxylic acid 5g (10 mg, 0.025 mmol) wasconverted to 7.3 mg of the title compound 7g.

[0106] Compound 7h

[0107] Isopropyl 7-[3 α,5α-Dihydroxy-2-(3α-hydroxy-5-(5-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoate.

[0108] According to the procedures described above for the preparationof 7f the previously prepared carboxylic acid 5h (10 mg, 0.025 mmol) wasconverted to 7.8 mg of the title compound 7h.

[0109] Compound 7i

[0110] Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoate.

[0111] According to the procedures described above for the preparationof 7f the 7-[3α,5α-Dihydroxy-2-(3α-hydroxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)-cyclopentyl]-5Z-heptenoicacid 5i (10 mg, 0.025 mmol) was converted to 7.0 mg of the titlecompound 7i.

[0112] Compound 11f

[0113] 7-[3α, 5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0114] Step 1: Methylation of C-15 Hydroxyl Group

[0115] Methyl triflate (MeOTF) (97 mL, 0.86 mmol) was added to asolution of the mixture of alcohols 8f (160 mg, 0.28 mmol) and2,6di-t-butyl-pyridine (0.22 mL, 1.00 mmol) in CH₂Cl₂ (1.5 mL) at 0° C.The reaction was then allowed to warm to room tempeature and stirringwas continued for 16 h. After quenching with saturated aqueous NaHCO₃the reaction was extracted with EtOAc. The organic portion was washedwith 1N HCl, brine, dried over MgSO4, filtered and concentrated invacuo. Flash column chromatography (silica gel, 4:1 hexane/EtOAc)provided 123 mg of the mixture of 15αa:, β-methyl ethers 9f.

[0116] Step 2: Removal of the Bis-Tetrahydropyranyl Protecting Groups

[0117] A solution of alcohols 9f (123 mg, 0.214 mmol) and pyridiniump-toluenesulfonate (40 mg, 0.16 mmol) in MeOH (3.0 mL) was heated at 40°C. for 4 h. The solvent was removed in vacuo. The residue was dilutedwith EtOAc and then washed with 1N HCl, saturated aqueous NaHCO₃ andbrine. The organic portion was dried over MgSO4, filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography (silica gel, 1:1 hexane/EtOAc followed by 100% EtOAc)gave 20.6 mg of 150:-methyl ether 10f.

[0118] Step 4: Preparation Carboxylic Acid 11f

[0119] The ester of 1Of (10 mg, 0.025 mmol) was diluted with THE (0.4mL) and lithium hydroxide (0.2 mL of a 0.5 N solution in H₂O, 0.05 mmol)was added. After 16 h the reaction was acidified with 1N HCl andextracted with EtOAc. The organic portion was washed with brine, driedover MgSO4, and concentrated in vacuo. The residue was purified by flashcolumn chromatography (silica gel, 9:1 MeOH/EtOAc) to furnish 5.0 mg ofthe carboxylic acid 11f.

[0120] Compound 11i

[0121] 7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoic acid.

[0122] According to the procedures described above for the preparationof 11f the mixture of alcohols 8i (295 mg, 0.50 mmol) were converted to9.4 mg of title compound 11i.

[0123] Compound 12f

[0124] Isopropyl 7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenote 12f.

[0125] A mixture of ester 10f (20 mg, 0.05 mmol) and potassium carbonate(20.4 mg, 0.15 mmol) in anhydrous isopropanol (3.0 mL) was heated at100° C. for 16 h. The reaction was concentrated in vacuo and the residueas stirred with 1:1 EtOAc/H₂O (˜20 mL) for 0.5 h. The organic portionwas separated, dried over MgSO4, filtered and concentrated in vacuo.Purification of the residue by flash column chromatography (silica gel,2:1 hexane/EtOAc) provided 20.2 mg of the title compound 12f.

[0126] Certain of the above compounds were tested for activity in thevarious in vitro assays described below and the results are reported inTables 1 and 2, below. TABLE 1 EC₅₀ (nM) IC₂₅ FP/EP₄ AGN-# FP EP₁ EP₃DP/EP₂ EP₄ Ratio

568 21190   0.03

0.8 23 0.03

24 23 1.0

0.25

1.4

2.2 165  0.01

291 3760  0.08

0.44

50

35 620  0.06 Platelets Dog IOP Hyp/ AGN-# TP aggreg inhib (1 day) Mlosis

692

>10⁴ 0.1%/−2.7 1.13/pinpoint

NA

0.1%/−2.1 0.75/pinpoint

NA 0.1%/−4.4 0.01%/−3.2 1.0/pinpoint 1.5/pinpoint

[0127] TABLE 2 EC₅₀ (nM) IC₂₅ FP/EP₄ AGN-# FP EP₁ EP₃ DP/EP₂ EP₄ Ratio

33 1630  0.02

4 57 0.07

5 100  0.05

Platelets Dog IOP Hyp/ AGN-# TP aggreg inhib (1 day) Mlosis

NA 0.1%/−3.6 0.6/pinpoint

[0128] Activity at different prostanoid receptors was measured in vitroin isolated smooth muscle preparations. FP-activity was measured ascontraction of the isolated feline iris sphincter. EP₄-activity wasmeasured as relaxation of smooth muscle of isolated rabbit jugular vein.TP-vasoconstrictor activity was measured as contraction of rings of theisolated rat thoracic aorta. Effects on platelets from healthy humandonors were measured by incubating platelet-rich plasma with thecompounds described herein. Inhibition of aggregation was determined bythe ability of the compounds described herein to inhibit plateletaggregation in platelet-rich plasma induced by 20 μM adenosinediphosphate (ADP).

[0129] Potential therapeutic applications of the compounds describedabove are in osteoporosis, constipation, renal disorders, sexualdysfunction, baldness, diabetes, cancer and in disorder of immuneregulation.

[0130] Many examples also have pronounced activity at the FP receptor,provisionally termed FP_(VASC) associated with the vascular endotheliumin the rabbit jugular vein preparation. Since such agents would bevasodilators they have potential in hypertension and any disease wheretissue blood perfusion is compromised. Such indications include, but arenot limited to, systemic hypertension, angina, stroke, retinal vasculardiseases, claudication, Raynauds disease, diabetes, and pulmonaryhypertension.

[0131] The effects of certain of the compounds of the working exampleson intraocular pressure are also provided in the following tables. Thecompounds were prepared at the said concentrations in a vehiclecomprising 0.1% polysorbate 80 and 10 mM tris (hydroxy methyl)aminomethane hydrochloride (TRIS) base. Dogs were treated byadministering 25 μl to the ocular surface, the contralateral eyereceived vehicle as a control. Intraocular pressure was measured byapplanation pneumatonometry. Dog intraocular pressure was measuredimmediately before drug administration and at 6 hours thereafter.

[0132] The compounds of the invention may also be useful in thetreatment of various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heat failure, andangina pectoris, in which case the compounds may be administered by anymeans that effect vasodilation and thereby relieve the symptoms of thedisease. For example, administration may be by oral, transdermal,parenterial, subcutaneous, intravenous, intramuscular, intraperitoneal,transdermal, or buccal routes.

[0133] The compounds of the invention may be used alone, or incombination with other of the known vasodilator drugs.

[0134] The compounds of the invention may be formulated into an ointmentcontaining about 0.10 to 10% of the active ingredient in a suitable baseof, for example, white petrolatum, mineral oil and petrolatum andlanolin alcohol. Other suitable bases will be readily apparent to thoseskilled in the art.

[0135] The pharmaceutical preparations of the present invention aremanufactured in a manner which is itself known, for example, by means ofconventional dissolving or suspending the compounds, which are alleither water soluble or suspendable. For administration in the treatmentof the other mentioned pathophysiological disorders. The pharmaceuticalpreparations which can be used orally include push-fit capsules made ofgelatin, as well as soft, sealed capsules make of gelatin and aplasticizer such as glycerol or sorbitol. The push-fit capsules cancontain the active compounds in liquid form that may be mixed withfillers such as lactose, binders such as starches, and/or lubricantssuch as talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds are preferably dissolved or suspended insuitable liquids, such as in buffered salt solution. In addition,stabilizers may be added.

[0136] In addition to being provided in a liquid form, for example ingelatin capsule or other suitable vehicle, the pharmaceuticalpreparations may contain suitable excipients to facilitate theprocessing of the active compounds into preparations that can be usedpharmaceutically. Thus, pharmaceutical preparations for oral use can beobtained by adhering the solution of the active compounds to a solidsupport, optionally grinding the resulting mixture and processing themixture of granules, after adding suitable auxiliaries, if desired ornecessary, to obtain tablets or dragee cores.

[0137] Suitable excipients are, in particular, fillers such as sugars,for example lactose or sucrose, mannitol or sorbitol, cellulosepreparations and/or calcium phosphates, for example tricalcium phosphateor calcium hydrogen phosphate, as well as inders such as starch, pasteusing for example, maize starch, wheat starch, rich starchy, potatostarch, gelatin, tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/orpolyvinyl pyrrolidone. If desired, disintegrating agents may be addedsuch as the above-mentioned starches and also carboxymethyl-starch,crosslinked polyvinyl pyrrolidone, agar, or algenic acid or a saltthereof, such as sodium alginate. Auxiliaries are, above all,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings which if desired, are resistant to gastric juices. Forthis purpose, concentrated sugar solutions may be used, which mayoptionally containing gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices, solutions of suitable cellulosepreparations such as acetylcellulose phthalate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tables or dragee coatings, for example, foridentification or in order to characterize combinations of activecompound doses.

[0138] Suitable formulations for intravenous or parenteraladministration include aqueous solutions of the active compounds. Inaddition, suspensions of the active compounds as oily injectionsuspensions may be administered. Aqueous injection suspensions maycontain substances which increase the viscosity of the suspensioninclude, for example, sodium carboxymethyl cellulose, soribitol, and/ordextran. Optionally, the suspension may also contain stabilizers.

[0139] The foregoing description details specific methods andcompositions that can be employed to practice the present invention, andrepresents the best mode contemplated. However, it is apparent for oneof ordinary skill in the art that further compounds with the desiredpharmacological properties can be prepared in an analogous manner, andthat the disclosed compounds can also be obtained from differentstarting compounds via different chemical reactions. For example, thepresent invention contemplates certain prodrugs and derivatives of theabove disclosed compounds, wherein R⁶ is

[0140] These compounds may be made by methods known in the art, i.e. theacetylation of the 1-hydroxy or 1-amino or 1-amido derivatives, etc.,disclosed above, with the appropriate acid chloride or acid anhydride.R⁶ may be

[0141] as well, when said 1-hydroxy, or 1-amino or 1amido derivativesare reacted with the appropriate ortho ester. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound useful for treating ocular hypertension represented byformula I:

wherein wavy line attachments indicate either the alpha (α) or beta (β)configuration; dashed bonds represent a double bond or a single bond, Ris a heteroaryl or a substituted heteroaryl radical, R¹ is hydroxyl orhydrocarbyloxy or hetero atom substituted hydrocarbyloxy comprising upto 20 carbon atoms, x is selected from the group consisting of —OR⁶ and−N(R⁶)₂ wherein R⁶ is selected from the group consisting of hydrogen, alower alkyl radical having from 1 to 6 carbon atoms,

wherein R⁵ is a lower alkyl radical having from 1 to 6 carbon atoms andy is ═O or represents 2 hydrogen radicals and further provided at leastone of R¹ is a hydrocarbyloxy or an heteroatom substitutedhydrocarbyloxy or a pharmaceutically-acceptable salt thereof.
 2. Themethod of claim 1 wherein said compound is represented by formula II

wherein the hatched segments represent α bonds and the solid trianglerepresents a β bond.
 3. The compound of claim 2 wherein the substituenton the heteroaryl radical is selected from the group consisting of loweralkyl, halogen, trifluoromethyl (CF₃), COR_(7,) COCF_(3,) SO₂NR_(6,)SO₂NH_(2,) NO₂ and CN, wherein R₇ is a lower alkyl radical.
 4. Thecompound of claim 2 wherein said compound is represented by formula III:

wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, or,together with

R³ and R⁴ forms a condensed aryl ring and R₅ is a lower alkyl havingfrom 1 to 6 carbon atoms.
 5. The compound of claim 4 wherein saidcompound represented by formula IV:


6. The compound of claim 5 wherein X is —OH or —NH_(2.)
 7. The compoundof claim 5 wherein Y is ═O and X is —OH.
 8. The compound of claim 5wherein Y is ═O and X is isopropoxy.
 9. The compound of claim 5 whereinZ is S.
 10. The compound of claim 5 wherein Z is O.
 11. The compound ofclaim 9 wherein said compound is 7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(3-(2-methyl)thienyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.
 12. The compound of claim 10 wherein said compound is 7-[3α,5α-Dihydroxy-2-(3a-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoicacid.
 13. The compound of claim 10 wherein said compound is Isopropyl7-[3α,5α-Dihydroxy-2-(3α-methoxy-5-(2-furanyl)-1E-pentenyl)cyclopentyl]-5Z-heptenoate.14. A method of treating systemic hypertensive and pulmonary disease orgastrointestinal disease, reproduction, fertility, incontinence, shock,inflammation, immune regulation, disorder of bone metabolism, renaldysfunction, cancer and hyperproliferative disease which comprisesadministering to a mammal having one of said diseases a therapeuticallyeffective amount of a compound represented by formula I

wherein wavy line attachments indicate either the alpha (α) or beta (β)configuration; dashed bonds represent a double bond or a single bond, Ris a heteroaryl or a substituted heteroaryl radical, R¹ is hydroxyl orhydrocarbyloxy or hetero atom substituted hydrocarbyloxy comprising upto 20 carbon atoms, X is selected from the group consisting of —OR⁶ and—N(R⁶)₂ wherein R⁶ is selected from the group consisting of hydrogen, alower alkyl radical having from 1 to 6 carbon atoms,

wherein R⁵ is a lower alkyl radical having from 1 to 6 carbon atoms andY is ═O or represents 2 hydrogen radicals and further provided at leastone of R¹ is a hydrocarbyloxy or an heteroatom substitutedhydrocarbyloxy or a pharmaceutically-acceptable salt thereof.
 15. Themethod of claim 14 wherein said compound is

wherein the hatched segments represent α bonds and the solid trianglerepresents a β bond.
 16. The method of claim 15 wherein said substituenton the heteroaryl radical is selected from the group consisting of loweralkyl, halogen, trifluoromethyl (CF₃), COR_(7,) COCF_(3,) SO₂NR_(6,)SO2NH2, NO₂ and CN, wherein R₇ is a lower alkyl radical.
 17. The methodof claim 15 wherein said compound is

wherein Z is selected from the group consisting of O and S, A isselected from the group consisting of N, —CH, and C, R² is selected fromthe group consisting of hydrogen, halogen and lower alkyl having from 1to 6 carbon atoms, R³ and R⁴ are selected from the group consisting ofhydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, or,together with

R³ and R⁴ forms a condensed aryl ring and R⁵ is a lower alkyl havingfrom 1 to 6 carbon atoms.
 18. The method of claim 17 wherein saidcompound is


19. The method of claim 18 wherein Z is S.
 20. The method of claim 18wherein Z is O.